Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking

Elkamhawy, Ahmed; Farag, Ahmed Karam; Viswanath, Ambily Nath Indu; Bedair, Tarek M.; Leem, Dong Gyu; Lee, Kyung‐Tae; Pae, Ae Nim; Roh, Eun Joo

doi:10.1016/j.bmcl.2015.10.003

Cited by 38 publications

(40 citation statements)

References 32 publications

(32 reference statements)

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“…Other compounds in this series all yield weaker cellular activities (>100 nM) against the NCI-H1975 cancer cell line. Taken together, the allenamide-containing analogues (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have high kinase inhibition activities for both double mutant and wild type EGFR kinases. However, the selectivity varies between double mutant and wild type EGFR kinasecontaining cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…[10][11][12] The clinical success of 1-3 and other TCIs has spurred a passion to search for other α,β-unsaturated carbonyls as bioisosteres of the acrylamide moiety in drug discovery. 2,3,5,9,13,14 For example, a but-2-ynamide moiety has been used as the warhead of 4 (acalabrutinib), which covalently bonds to the Cys-481 residue of BTK and was recently approved by the FDA for treating mantle cell lymphoma. 11,15 Another earlier example, 5 (ethacrynic acid), has also been approved for the treatment of high blood pressure and swelling for more than 30 years, and it is currently being investigated in clinics for the treatment of bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

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Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

et al. 2018

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The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, , inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. also inhibited the growth of NCI-H1975 lung cancer cells at IC = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with . By measuring the conjugate addition product formed by and GSH, we obtained a reaction rate constant of 302.5 × 10 min, which is about 30-fold higher than that of osimertinib. Taken together, our data suggest that the allenamide-containing compounds inhibited EGFR kinases through covalent modifications. Our study indicates that the allenamide group could serve as an alternative electrophilic warhead in the design of targeted covalent inhibitors, and this bioisostere replacement may have broad applications in medicinal chemistry.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

et al. 2018

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“…Modern studies typically build models of inhibitor-bound structures via docking: sampling all possible locations and orientations for the inhibitor, then selecting the best-scoring binding mode from among these many possibilities [32][33][34][35][36][37][38][39][40]. In contrast, and by analogy to protein structure prediction, we anticipated that the PDB's continuously growing body of structural information could serve as the basis for building more accurate models via comparative modeling.…”

Section: Overview Of the Comparative Modeling Pipelinementioning

confidence: 99%

Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

Kirubakaran

Morton

Zhang

et al. 2020

Preprint

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Cyclin-dependent kinase 9 (CDK9) plays a key role in transcription elongation, and more recently it was also identified as the molecular target of a series of diaminothiazole compounds that reverse epigenetic silencing in a phenotypic assay. To better understand the structural basis underlying these compounds' activity and selectivity, we developed a comparative modeling approach that we describe herein. Briefly, this approach draws upon the strong structural conservation across the active conformation of all protein kinases, and their shared pattern of interactions with Type I inhibitors.Because of this, we hypothesized that the large collection of inhibitor/kinase structures available in the Protein Data Bank (PDB) would enable accurate modeling of this diaminothiazole series in complex with each CDK family member. We apply this new comparative modeling pipeline to build each of these structural models, and then demonstrate that these models provide retrospective rationale for the structure-activity relationships that ultimately guided optimization to the lead diaminothiazole compound MC180295 (14e). We then solved the crystal structure of the 14e/CDK9 complex, and found the resulting structure to be in excellent agreement with our corresponding comparative model. Finally, inspired by these models, we demonstrate how structural changes to 14e can be used to rationally tune this compound's selectivity profile. With the emergence of CDK9 as a promising target for therapeutic intervention in cancer, we anticipate that comparative modeling can provide a valuable tool to guide optimization of potency and selectivity of new inhibitors targeting this kinase.anti-tumoral activity coupled with immunosensitization [28]. With respect to selectivity, the preference of 14e for CDK9 over CDK2 and CDK7 was especially notable: due to their structural and functional similarities, most CDK9 inhibitors also inhibit CDK2 and CDK7 [29,30]. In our first study, we explored selectivity of 14e by developing a comparative modeling approach to build a model of the 14e/CDK9 complex, and then using this model to propose a structural basis for the observed selectivity [28].In the present study we expand our understanding of the structure-activity relationship (SAR) of the series and use these data to critically evaluate our comparative modeling approach. In particular, we present the SAR of 77 compounds related to 14e, and retrospectively assess the extent to which comparative modeling could have driven optimization. We also characterize 14e selectivity further, in light of a recent study demonstrating the surprising lack of selectivity in compounds ostensibly selective for other CDKs [6], and a report summarizing the broad selectivity profiles of CDK9 inhibitors that have advanced to clinical trials [22]. Finally, to definitively evaluate the accuracy of our comparative modeling for this application, we solve the crystal structure of 14e in complex with CDK9. Results and DiscussionOur previous study culminated with the identification and c...

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“…Lately, it has been observed that benzo[g]quinazoline and sulphonamides demonstrated profound growth inhibitory activity against different cancer cells and TK enzymes 14 , 15 . The quinazoline is a privileged scaffold that constitutes an important class of heterocyclic compounds owing to its varies pharmacological properties 16 , 17 . Afatinib, lapatinib, gefitinib, and erlotinib (Figure 1) are the representative drugs in this class in clinical use for targeted anticancer therapies 18–21 .…”

Section: Introductionmentioning

confidence: 99%

Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

Soliman

Alqahtani

Ghorab

2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of sulphonamide benzoquinazolinones 5–18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC 50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC 50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC 50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.

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Targeting EGFR/HER2 tyrosine kinases with a new potent series of 6-substituted 4-anilinoquinazoline hybrids: Design, synthesis, kinase assay, cell-based assay, and molecular docking

Cited by 38 publications

References 32 publications

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors

Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

Novel sulfonamide benzoquinazolinones as dual EGFR/HER2 inhibitors, apoptosis inducers and radiosensitizers

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